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Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18.

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Autoimmunity: From Bench to Bedside [Internet].

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Chapter 26Antiphospholipid syndrome

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Introduction

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder defined by the persistent presence of antiphospholipid antibodies (aPL) in plasma of patients with vascular thrombosis and/or pregnancy morbidity. APL are formally detected by functional coagulation assay (the so called lupus anticoagulant LAC) and/or by solid phase assays: anti-cardiolipin (aCL) or anti-β2glycoprotein I (anti-β2GPI) antibody tests.

The clinical features and laboratory manifestations associated with aPL have broadened considerably since the first description of APS in 1983 (1) and now include thrombocytopenia, hemolytic anemia, cardiac valve disease, pulmonary hypertension, microangiopathic nephropathy, skin ulcers, livedoreticularis, refractory migraine, cognitive dysfunction, and atherosclerosis (2).

Classification criteria for APS were developed at the 1998 antiphospholipid antibodies congress (8th APLA) and have recently been updated (3). APS is defined by the presence of at least one of the clinical criteria and one of the laboratory criteria. The criteria define patients with “primary” or isolated APS (PAPS) as those with the diagnosis in the absence of any underlying autoimmune disease, and patients with “secondary” APS (SAPS) as those with another autoimmune disorder associated, aPL and the clinical manifestations of the syndrome (3).

A variant of APS characterized by acute thrombotic microangiopathy with subsequent multiorgan failure and high mortality has also been identified: the so-called catastrophic APS (CAPS). (4) Probable and microangiopathic APS are additional disease subsets that have been suggested but not yet formally accepted (4).

There have been recent changes in the management and diagnosis of APS and in current opinions on its pathogenesis. The aim of this chapter is to provide an update on recent insights into the epidemiology, pathophysiology, diagnosis, and treatment of APS.

Epidemiology

A cumulative, retrospective, literature analysis indicates that approximately 30% to 40% of patients with aPL have a history of thrombosis and that 30% of the events are of the arterial bed (5). Cerebral circulation is the most commonly affected arterial region while the coronary arteries and other arterial regions are less frequently reported (6). A meta-analysis of case-control, cross-sectional, and retrospective-prospective studies of the association between LAC, IgG/IgM aCL, and arterial thrombosis reported a strong association with LAC (odds ratio up to 10) while a much-weaker association was found for aCL. In general, only the aCL IgG isotype and moderate/high antibody titers (i.e. >40 GPL units) were significantly associated with arterial thrombosis (first cerebral stroke or myocardial infarction) (7). Arterial events are also the most frequent recurrences, even in already diagnosed and treated APS patients, as reported in the 5-year follow-up on the European series. Specifically, strokes (2.4% of the total cohort) and transient ischemic attacks (2.3%) were the most frequent recurrent manifestations. In addition, myocardial infarction (18.9%) and stroke (13.2%) were also causes of mortality in the same series (8).

Venous thrombosis (VT), usually deep vein thrombosis (DVT), is the most common clinical manifestation of APS and occurs in more than 30% of the patients (9). The frequency of aPL in venous thrombosis is reported to range from 5.2% to 30% for any aPL, 0.6–16% for LAC, and 4–24% for aCL (10). Prospective studies of the general population have shown that aPL are predictive of a first DVT, recurrent thromboembolism, and death (11). Elevated anti-β2GPI IgG significantly reduces the OR for venous thromboembolism (VTE) by about five-fold (OR: 5.2, 95%CI: 1.5–18) and displays a stronger risk association for VTE than elevated aCL IgG (12).

Pregnancy complications have been observed in aPL-positive women (10–19%) (9). A significantly increased prevalence of IgG anti-β2GPI was found in pregnancies complicated by preeclampsia–eclampsia (up to 10%). LAC has been associated with late recurrent fetal loss (OR: 7.79, 95%CI 2.30–26.45). This association was stronger than that for any other aPL. When all titers were combined, IgG aCL were associated with both early (OR: 3.56, 95%CI: 1.48–8.59) and late, recurrent fetal loss (OR: 3.57, 95%CI: 2.26–5.65) (13).

APS can occur in association with other systemic autoimmune diseases, especially systemic lupus erythematosus (SLE). The prevalence of aPL in patients with SLE ranges from 12% to 44% for aCL, 15% to 34% for LAC, and 10% to 19% for anti-β2GPI. Longitudinal studies show that APS may develop in 50 to 70% of patients with both SLE and aPL after 20 years of follow-up (9, 14, 15).

APL can be found in apparently healthy control subjects with a prevalence ranging from 1 to 5% for both aCL and LAC although at low titers in most cases (10). An increased prevalence of antibodies detectable by all assays has been reported with ageing (16).

Since an association between aPL and syphilis was first described, many other viral, bacterial, and parasitic infections have been shown to induce aPL. The most common infections associated with aPL include hepatitis C virus, human immunodeficiency virus (HIV), cytomegalovirus, varicella-zoster, Epstein–Barr virus, adenovirus, and parvovirus B19 with a prevalence of up to 49% in HIV infections. In most infections, the antibodies found were β2GPI independent and thus did not interfer with anticoagulation, but there are some exceptions. With respect to bacterial infections, aCL are often present in leprosy (42.7%), where they frequently display anti-β2GPI activity (44.8%), and in syphilis infections (8 to 67%). Antiphospholipid antibodies associated with infections are usually transient and followed by APS clinical manifestations only in exceptional cases (17).

Active vaccination may induce the production of autoantibodies, including aPL. However, reports are anecdotal and the antibodies usually transient, at low titers, and with no relationship to clinical manifestations. In other cases, a cause-effect relationship between infections and the development of CAPS or thrombotic events in APS patients has been suggested (18).

APL can be found in a high percentage of children without any underlying disorder with an estimated frequency that ranges from 3 to 28% for aCL and 3 to 7% for anti-β2GPI. The reason for this frequent occurrence in comparison to adults is suggested to be the frequent infectious processes that occur during childhood (19).

Pathophysiology of thrombosis in APS

Multiple molecular pathways are implicated in the pathogenesis of APS. The mechanisms of thrombosis production in patients with APS are not completely clear. However, the interaction between aPL and cells involved in the regulation of hemostasis is one of the mechanisms responsible for the thrombophilic state in APS. Current evidence suggests that inhibition of physiological anticoagulant pathways, impairment of fibrinolysis, and promotion of clot formation result in thrombus formation in APS (20).

Despite the persistent presence of aPL in the circulation, thrombotic events in patients with aPL only occur occasionally, suggesting that the presence of aPL is necessary but not sufficient for clot formation in vivo. The ‘two-hit hypothesis’ has been proposed in which aPL (first hit) can only exert their prothrombotic influence in the presence of another thrombophilic condition (second hit). This ‘two-hit hypothesis’ was demonstrated in an animal model of APS in which the injection of aPL in rats only resulted in increased thrombus formation when rats were pre-treated with lipopolysaccharide (LPS), but not when they were injected with pure buffer (21).

The major antigen structures recognized by aPL in patients with APS are phospholipid-binding proteins, β2GPI and prothrombin, which are expressed on the membranes of different cell types. The antibody forms a complex with the corresponding antigen which leads to cell perturbation, activation of cell signaling pathways, transcription of pro-coagulant substances, adhesion molecules and, subsequently, thrombus formation. Table 1 shows aPL-mediated pathogenic mechanisms. aPL are reported to have heterogeneous interactions with endothelial cells, monocytes, and platelets (22). Antibodies directed against plasma protein ß2GPI are considered the most clinically significant as several studies have shown this aPL is strongly related to thrombosis. ß2GPI is a plasma protein that consists of five domains. Recent studies have unveiled domain I of ß2GPI as an integral component of the pathogenicity of this protein (23). The interaction of ß2GPI with phospholipids induces major conformational changes in this protein which expose hidden epitopes within domain I. Point mutations within domain I were shown to abrogate binding of anti-ß2GPI (24, 25). It was confirmed that anti-ß2GPI with specificity to domain I increases susceptibility to venous thrombosis (24).

Table 1. Antiphospholipid antibody (aPL)-mediated pathogenic mechanisms.

Table 1

Antiphospholipid antibody (aPL)-mediated pathogenic mechanisms.

Nitric oxide (NO) produced by eNOS facilitates the prevention of thrombosis. The activation of eNOS is pertinent in preventing thrombosis as it inhibits platelet aggregation and down regulates adhesion molecules involved in clot formation. It is postulated that aPL may interfere in the activation of eNOS and subsequent NO production (26).

A number of findings suggest that the antiphospholipid syndrome is characterized by greater oxidative stress. Paraoxonase activity, which accounts for the antioxidant properties of high-density lipoprotein cholesterol [preventing oxidation of low-density lipoprotein (LDL) cholesterol], is significantly lower in people with the syndrome (27, 28), whereas levels of 8-epi-prostaglandin F2, a biomarker of lipid peroxidation, are elevated (29).

Plasma levels of ß2GPI–oxidized LDL complexes are elevated in patients with APS as compared to healthy controls (30). Oxidative stress plays a direct role in the structure and function of ß2GPI in patients with APS (31).

Pathophysiology of pregnancy morbidity in APS

The pathogenesis of obstetric APS is not fully known although studies have suggested the involvement of complement, ß2GPI, and annexin V. Some observational studies of women with obstetric APS events have shown cases with no evidence of placental thrombosis, infarctions, or vasculopathy which suggests that APS should be redefined as an inflammatory disorder (32).

Murine models strongly suggest the involvement of complement activation in the pathophysiology of pregnancy morbidity in patients with APS. Preliminary data from recent reports indicate that the histology of placental specimens from patients with APS shows evidence of complement activation compared to control placental specimens. However, complement deposition can be detected in both abortive specimens and placentas at term without a clear relationship with either pregnancy outcome, or therapy (33). Although extensive prospective analyses are needed to demonstrate definitive results regarding the involvement of complement in APS-related pregnancy morbidity, the potential role of complement in aPL-mediated clinical manifestations should not be neglected. In addition to causing acute local inflammation, complement components are able to modulate the functions of pro-coagulant cells (monocyte, endothelial cells) and decidual or trophoblastic cells (34).

The ß2GPI-dependent aPL mechanism of action is thought to involve recognition of the antigen on placental tissues, growth inhibition, and differentiation of trophoblasts, resulting in defective placentation (20). TIFI, a cytomegalovirus-derived synthetic peptide was shown to inhibit binding of ß2GPI-dependent aPL and, therefore, expression at a placental level and trophoblast modulation mediated by autoantibodies (35).

Rand et al. (36, 37) shed new light on the role of annexin A5, a potent anticoagulant protein that is expressed on the apical membranes of placental villous syncytiotrophoblasts at the interface between the fetus and placenta, endothelial cells, and platelets (36, 37). The protein plays a thrombomodulatory role by shielding phospholipidbilayers and blocking their availability for coagulation reactions. Competitive displacement by aPL IgG-ß2GPI immune complexes interferes with annexin A5 binding which leads to accelerated coagulation and contributes to pregnancy loss and thrombogenic effects. Hydroxychloroquine (HCQ) reduces the exposure of thrombogenic phospholipids by inhibiting and reversing aPL IgG-ß2GPI complex formation and promoting the formation of annexin V secondary patches in areas of disrupted aPL IgG-ß2GPI immune complexes.

Clinical manifestations

Thromboses are one of the hallmarks of APS, and venous thrombosis, or embolism, is the most frequent manifestation (2). However, in contrast to thromboses associated with congenital thrombophilias, those associated with APS may also occur in any vascular bed. In the arterial bed, the CNS is most generally affected (2), usually in the form of stroke or transient ischemic attacks. APL have also been associated with venous sinus thrombosis, myelopathy, chorea, migraine, and epilepsy (38), aCL have been linked to cognitive impairment in patients with SLE (39). Similarly, mild cognitive dysfunction has been recorded in more than 40% of patients with APS along with a strong association with cerebral white matter lesions (40). Multiple sclerosis-like CNS lesions and compatible clinical presentations have been noted in a subset of patients with APS (41).

aPL are associated with cardiac valvular disease. The mitral valve is most frequently affected followed by the aortic valve (42). Regurgitation is more common than stenosis, and many patients remain asymptomatic for years. Acute coronary syndromes are much less prevalent than cerebrovascular disease (2). Renal involvement in APS was first described in 1992 (43). Thrombotic microangiopathy is the most characteristic finding but fibrous intimal hyperplasia, focal cortical atrophy, and arterial occlusions have also been described (44). Hypertension with proteinuria (often subnephrotic) and renal failure are typical presentations of APS nephropathy (43, 44). Renal artery stenosis can also present as refractory hypertension (45).

Other clinical features associated with aPL are, in order of frequency, thrombocytopenia, hemolytic anemia, skin ulcers, avascular bone necrosis, and adrenal insufficiency (2). Livedo reticularis is present in about a quarter of the patients with APS and is a physical sign that should lead to clinical suspicion of APS in the appropriate clinical context. Moreover, livedo reticularis may be a marker for patients at high risk for arterial thrombosis (46).

The most severe and, fortunately, infrequent form of APS is CAPS. There is usually a triggering factor that induces widespread small-vessel thrombosis with multiorgan failure and a mortality rate in the short-term of more than 50% (47).

Obstetric complications are the other hallmark of APS with the most common manifestation being recurrent miscarriage, which is usually defined as three or more consecutive miscarriages before the mid-second trimester and with most losses occurring before the 10th week of gestation. Other obstetric features of APS are one or more fetal deaths occurring at or beyond the 10th week of gestation, severe preeclampsia, or placental insufficiency prompting delivery at more than 34 weeks gestation (2, 48). In a retrospective study, women with obstetric APS were at high-risk of subsequent thrombotic complications (49).

Classification and diagnosis

The current guidelines for the classification of APS rely upon clinical and laboratory criteria. They were designed to restrict confirmed cases rather than include doubtful ones. For diagnostic purposes, they may not always be applied. There are several situations that may not meet criteria and require a management decision including thrombocytopenia, hemolytic anemia, and the decision to do a skin, kidney, or liver biopsy as well as the cases of when there is a typical clinical picture with no laboratory aPL detected, the so-called seronegative APS (SNAPS). The clinical classification criteria include the presence of vascular and/or obstetric complications. Clinical manifestations are often nonspecific to APS and highlight the importance of including the laboratory definition in the classification criteria (50). The 2006 Sydney APLA Congress consensus concluded that persistent positivity of LAC and/or aCL antibodies, or anti-ß2GPI on two separate occasions, 12 weeks apart, would be required for the revised classification criteria of APS (Table 2). Additionally, the consensus recommended the use of a clotting assay for the detection of LAC and an ELISA technique for the detection of aCL and anti-ß2GPI (3). The serological criteria that define APS are fraught with limitations largely due to the lack of standardization in the above named techniques. This results in significant inter-assay and intra-assay variation and potentially over/under diagnosis of APS (50). Patients misdiagnosed with APS may be at imminent risk of bleeding due to unnecessary thrombolysis (51). In view of this, lupus anticoagulant detection guidelines were revised and published to address this issue. (52) Lakos et al. (53) recently formulated long-awaited consensus recommendations for the detection of aCL and anti-ß2GPI.

Table 2. Revised classification criteria for the antiphospholipid syndrome.

Table 2

Revised classification criteria for the antiphospholipid syndrome.

The international consensus criteria were originally designed for scientific clinical studies and were never intended for diagnostic use. Consequently, there remains a need for firm diagnostic criteria for routine clinical use, which may differ from these. Gardiner et al, reported on serological criteria in a cohort of patients diagnosed to have APS based on a comprehensive methodological approach, which included testing for LA as well as IgG, IgMaCL, and antiß2GPI. They found that LA, aCL, and antiab2GPI testing are all required for the accurate diagnosis of APS and that low-titer antibodies should be included in the diagnosis of obstetric APS (54).

A recent study by Otomo et al. (55) formulated a score to quantify the risk of thrombosis/obstetric events in a cohort of patients with various autoimmune diseases. A score was given weighted on the relative risk of clinical manifestations of APS for each aPL assay. The assays were totaled to give the overall complete aPL-score. Otomo et al. (55) state that combining assays will compensate for the lack of standardization of single assays. High aPL-scores strongly correlated with reported thrombotic or obstetric events in this cohort, and thus have potential to be used as a marker for the probability of having APS. The score has a predictive value for new onset or recurrence of thrombosis in autoimmune disease. This creates an avenue for its use in management of APS as treatment can be modified based on a patient’s score. The complete score incorporates the phosphatidylserine-dependent antiprothrombin antibody (aPS/PT) assay, which was not formerly part of the conventional serological criteria and thuse limits its use clinically. A partial-aPL score was formulated which incorporated conventional assays. There was a correlation between higher scores and history of thrombosis/obstetric events although the association was not as strong as the complete score.

Conventional laboratory criteria may not allow proper detection of subsets of patients with what is currently called seronegative APS (SNAPS), who are persistently negative for routine assays detecting LAC, aCL, and anti-ß2GP1 antibodies but harbor clinical manifestations suggestive of APS (56). Routine antibody screening tests for the diagnosis of APS fail to identify cases of seropositive APS as other antibodies, e.g., the IgA isotype aCL and anti-ß2GP1, anti-phosphatidylserine, prothrombin, phosphatidylethanolamine, annexin V, and vimentin/cardiolipin complex do not have standardized assays and are not part of the classification criteria (57). Vimentin/cardiolipin antibodies may have a potential diagnostic and pathogenic role in patients with clinical manifestations of APS but do not conform to the conventional serological criteria (57).

Catastrophic antiphospholipid syndrome

CAPS was first described by Asherson in 1992 (58) and is characterized by multiple vascular occlusive events presenting over a short period of time in aPL-positive patients. It is an uncommon presentation that occurs in <1% of APS patients and often after a triggering factor such as anticoagulation withdrawal, surgery, minor surgical procedures, or infections. The mortality rate is around 50% and treatment includes corticosteroids, anticoagulation, intravenous immunoglobulin (IVIG), rituximab, eculizumab, and plasma exchange (59). The etiopathogenesis of catastrophic APS remains incompletely understood. Several mechanisms have been suggested such as molecular mimicry, infections, and activation of endothelium in the microvasculature and microvascular occlusions. (60) Kitchens et al. (61) have suggested that the vascular occlusions are themselves responsible for the continuum of thrombosis. Clots increasingly generate thrombin, fibrinolysis is impaired by the excess of plasminogen activator inhibitor type-1 (PAI-1), and there is consumption of the natural anticoagulant proteins such as protein C and antithrombin. These multiple small vessel occlusions cause extensive tissue necrosis which results in a systemic inflammatory response syndrome (SIRS) with excessive cytokine release from affected and necrotic tissues (62). Pro-inflammatory cytokines, several products of the activated complement system (e.g., C3b, iC3b, and C5a), and aPL themselves have each been shown to activate endothelial cells, provide a stimulatory signal, and up-regulate adhesion molecules and tissue factor. These molecules can also act on leukocytes and platelets to increase their adhesion to vascular endothelium and promote microthrombosis and the local release of toxic mediators including proteases and oxygen-derived free radicals. The interaction between all these cells in the presence of aPL leads to the diffuse microvasculopathy that characterizes CAPS and results in multi-organ failure (60, 62, 63). The most common known trigger for CAPS is infection. Less common causes are anticoagulation withdrawal or low international normalized ratio (INR), medications (e.g., oral contraceptive), obstetric complications, neoplasia, SLE flares, trauma, and surgery. Nevertheless, in almost half of the cases, no obvious precipitating factors have been identified, and CAPS can often occur in patients without any previous thrombotic history (59). The clinical manifestations of CAPS depend on the organs affected, the thrombotic events, and the extent of the thrombosis together with manifestations of SIRS. In contrast to classic APS, single venous or arterial medium-to-large blood vessel occlusions are uncommon in patients with CAPS. Multiple organ dysfunction and failure, as a consequence of thrombotic microangiopathy, are responsible for the majority of clinical features. However, large venous or arterial thrombosis can also occur in about one-fifth of patients.

The diagnosis of CAPS can be challenging due to the acute onset of thrombosis at multiple levels with simultaneous dysfunction of different organs. Patient survival very much depends on an early diagnosis and treatment. Preliminary CAPS classification criteria (Table 3) were proposed and agreed on at the 2002, APLA Congress in Taormina (Sicily) during the 10th International Congress on aPL. Although these criteria are accepted for classification purposes, they might also be used as a guide to a more consistent diagnostic approach (64). An update of the diagnostic algorithm for CAPS was recently proposed (65) and discussed by the Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations at the 13th International Congress on Antiphospholipid Syndrome, held in Galveston (Texas) in 2011 (66). This approach represents a step forward in the diagnosis of CAPS but must be validated versus other thrombotic microangiopathies.

Table 3. International classification criteria for CAPS.

Table 3

International classification criteria for CAPS.

To diagnose CAPS, there should be clinical evidence of multiple organ involvement over a short period of time, histopathological evidence of multiple small vessel occlusions, and laboratory confirmation of aPL, usually in high titers. The positivity of aPL should also be confirmed later when the acute clinical situation is resolved. aPL may also be positive in sepsis and other critical situations, which share several clinical features with CAPS. A differential diagnosis should be made with sepsis, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), acute disseminated intravascular coagulation (DIC) and hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome.

Treatment

APS is characterized by recurrent thrombotic events that have not been properly managed. Thus anti-thrombotic medication is necessary for long-term management to reduce thrombotic risk or pregnancy morbidity. Choosing the type of pharmacological treatment and the intensity and duration of anticoagulation depends on the clinical type, co-morbidities, severity of the APS, and the risk of bleeding. Change of life habits that are known to increase the risk of thrombotic events has to be stressed in addition to avoiding estrogens and cigarette smoking. When present, the active control of elevated serum LDL-cholesterol and triglycerides, arterial hypertension, and blood sugar, is recommended.

Patients with APS may be evaluated in an outpatient setting. In patient evaluation is required if the patient presents with a significant clinical event. Patients with CAPS require intense observation and treatment, often in the intensive care unit.

Venous thromboembolism

Venous thromboembolism is the most common initial clinical manifestation in APS and occurs in 32% of patients who meet consensus conference diagnostic criteria (67).

Initial treatment consists of unfractionated or low molecular-weight heparin for at least 5 days overlapped with warfarin therapy (68).

The use of warfarin with an international normalized ratio (INR) of 2.0- 3.0 reduces the risk of recurrent venous thrombosis by 80% to 90% irrespective of the presence of aPL (69). For long-term treatment of venous thromboembolism, retrospective case series have suggested that high-intensity warfarin (INR 3.0) is more effective than either aspirin or warfarin administered with an INR < 3.0 (70, 71).

Some studies have found that high-intensity warfarin is better than moderate-intensity warfarin for the prevention of recurrent thrombosis. However, a significant excess of minor bleeding was evident in patients who were given high-intensity warfarin (72).

Arterial thromboembolism

Arterial events in APS most commonly involve the cerebral circulation with stroke being the initial clinical manifestation in 13% and a transient ischemic attack in 7% of patients. (73) The association between APS and other arterial thrombosis, including myocardial infarction, is less certain.

Warfarin and aspirin appear to be equivalent for the prevention of thromboembolic complications in patients with a first ischemic stroke and aPL. Patients with a first ischemic stroke and a single positive antiphospholipid antibody test result who do not have another indication for anticoagulation may be treated with aspirin (325 mg/d) or moderate-intensity warfarin (INR, 1.4 - 2.8) (73). Aspirin is likely to be preferred because of its ease of use and lack of need for laboratory monitoring.

It is known that aPL may persist in the serum of APS patients for long periods of time, but thrombotic events occur only occasionally. It has been suggested that aPL (‘first hit’) raises the thrombophilic threshold (i.e., induces a prothrombotic/proinflammmatory phenotype in endothelial cells), but that clotting only takes place in the presence of a ‘second hit’ or triggering event (i.e., an infection, a surgical procedure, use of estrogens, prolonged immobilization, etc.) (74).

In general, treatment regimens for APS must be individualized based on the patient’s current clinical status, presence of co-morbidities, and history of thrombotic events. Asymptomatic individuals in whom blood test findings are positive do not require specific treatment in addition to avoidance of known risk factors.

Prophylactic therapy

  • Eliminate other risk factors such as oral contraceptives, smoking, hypertension, hyperhomocysteinemia, or hyperlipidemia.
  • Low-dose aspirin is usually used. Clopidogrel may be useful in patients allergic to aspirin.
  • In patients with SLE, consider HQC, which may have intrinsic antithrombotic properties.
  • Consider the use of statins, especially in patients with hyperlipidemia.

Initial therapies

Heparin. The initial approach to thrombosis in APS is identical to that of many other thromboses. For acute thrombotic events, the first therapy is heparin. Low molecular weight heparin (LMWH) has replaced unfractionated heparin as the standard of care for most thrombotic events.

Full dose LMWH (1mg/Kg twice daily) is usually given simultaneously with warfarin and is overlapped with warfarin for a minimum of four to five days until the International Normalized Ratio (INR) has been within the therapeutic range (2.0 to 3.0) for two consecutive days (72).

Some characteristics of heparin:

  • The antithrombotic effects include potentiating the anti-thrombin effects of antithrombin and other endogenous antithrombin effectors, increasing the levels of factor Xa inhibitor, and inhibiting platelet aggregation.
  • Heparin may also bind to aPLs and render them inactive (75).
  • Heparin may also block tissue factor-mediated placental bed immunopathology (76, 77).
Low molecular weight heparin. Several LMWH products are now available for clinical use. Dosing requirements are individualized for each product (78). The advantages of LMWH over unfractionated heparin are reviewed separately.

Unfractionated heparin. Unfractionated heparin is preferred to LMWH in certain circumstances. The major potential advantage of unfractionated heparin over LMWH is in the setting of hemorrhage (a rare complication of the APS). Unfractionated heparin can be reversed quickly with protamine while LMWH is not completely reversible with this approach. The major condition in which hemorrhage is due to APS is when antibodies to prothrombin are present.

Warfarin. Following stabilization of the patient, warfarin is begun. Warfarin is the standard of care for the chronic management of patients with APS who are not pregnant. INR should be maintained between 2.0 and 3.0 (79). However, aPL may create problems in monitoring the INR. A monotonous diet with only slight variations in the amount of vitamin K intake, intensification of monitoring when a different medication has to be used, and above all, patient education on the importance of close monitoring are crucial for the APS management to succeed.

Antiplatelet agents

Aspirin. Aspirin is of minimal or no benefit for the prevention of thrombotic APS manifestations in patients who have experienced previous events according to retrospective series (80). However, some studies suggest that aspirin (81 mg/day) reduces the risk of thrombosis in aPL- positive patients (81). In addition to its antiplatelet effects, low dose aspirin (ASA) (50 to 100 mg) enhances leukocyte-derived interleukin-3 production, which stimulates normal trophoblast growth and hormone expression (82).

Retrospective and prospective observational studies and controlled trials of aspirin for the prevention of thrombotic events in people with aPL with no history of arterial or venous thromboembolism have had disparate results (82, 83). The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study consisted of two separate investigations involving patients who were asymptomatic but persistently aPL-positive (84). The conclusions of the APLASA trial were:

  • Asymptomatic individuals who are persistently positive for aPL have a low annual incidence of acute thrombosis.
  • These individuals do not benefit from low-dose aspirin.
  • Thrombotic events in this population are unlikely in the absence of additional risk factors for thrombosis.
Clopidogrel. It has anecdotally been reported to be helpful in patients with APS and may be useful in those allergic to aspirin. Its use is not advised for the treatment of APS (85).

Current treatment of thrombosis

Treatments in APS are directed at modulating the final event or second hit. Treatments that modulate the early effects of aPL on target cells – that is monocytes or endothelial cells (first hit) – would be more beneficial and potentially less harmful than current treatments.

The current antithrombotic approach to aPL-positive patients may be replaced by an immunomodulatory approach in the future as our understanding of the mechanisms of aPL-mediated thrombosis improves. Understanding the molecular mechanisms triggered by aPL and identifying biomarkers released as a consequence of cell activation may help us design new ways to treat clinical manifestations in APS.

The main target recognized by aPL binds to endothelial cells and monocytes through its fifth domain. aPL/anti-β2GPI antibodies then bind to domain I of β2GPI, and upon clustering and formation of complexes, they trigger cell activation (86-88).

Therefore, blocking the binding of aPL or inhibiting the binding of β2GPI to target cells may be the most specific approach to ameliorate their pathogenic effects without interrupting any important physiologic mechanisms. Recently, Ioannou et al. demonstrated that the soluble recombinant domain I of β2GPI abrogates, in a dose-dependent fashion, the in vitro and in vivo effects of anti-β2GPI antibodies. This underscores the possibility of utilizing decoy peptides that are part of β2GPI to abrogate the binding of pathogenic aPL to target cells in the treatment of patients with APS. Nevertheless, human studies are needed to establish the safety and efficacy of such a treatment (89, 90).

GPIIbIIIa inhibitors

aPL-enhanced thrombosis in vivo can be abrogated by infusions of a GPIIb/IIIa antagonist monoclonal antibody. Recently, it has been reported that heterozygosity for platelet glycoproteinsIa/IIa and IIb/IIIa increase arterial thrombosis in patients with APS (91). These data indicate that GPIIb/IIIa antagonists or platelet membrane glycoprotein IIb/IIIa receptor inhibitors may prove to be useful in the treatment of an acute thrombotic event, particularly an arterial event, in patients with APS. In addition, the combination of GPIIb/IIIa antagonists and an ADP receptor antagonist, e.g., ticlopidine, is an attractive therapeutic strategy. It provides fast and continuous platelet inhibition since pre-stimulation of platelets by agonists leads to the exposure of phosphatidylserine on the outer membrane of the cell. As a result, it produces an anti-β2GPI/β2GPI complex on the exposed phosphatidylserine before interacting with a specific platelet receptor to potentiate activation (92-94).

Hydroxychloroquine (HCQ)

HCQ inhibits the aPL-induced expression of platelet GPIIb/IIIa receptor (platelet activation) dose-dependently and also reverses the binding of aPL–β2GPI complexes to phospholipidbilayers (95). In SLE patients, those receiving HCQ experienced fewer thrombotic events and results from the Baltimore Lupus Cohort showed a decreased risk of arterial thrombosis (95). HCQ could be used in patients with APS and thrombosis as a second-line agent together with anticoagulation therapy. We still do not have a study result for a consistent recommendation for HCQ in APS although, in SLE, it is known to reduce the thrombotic risk, including during pregnancy.

Rituximab (RTX)

RTX has been shown to be a good treatment for life-threatening CAPS in a few patients and case reports suggest it may be successful in patients with aPL, autoimmune-mediated thrombocytopenia, and hemolytic anemia. Statkute et al. demonstrated normalization of aCL antibody titer after autologous hematopoietic stem-cell transplantation in patients with APS secondary to SLE (97-100). Recently, an uncontrolled and nonrandomized pilot study suggested that the safety of rituximab in aPL-positive patients with non-criteria manifestations of APS is consistent with the safety profile of rituximab. Despite causing no substantial change in aPL profiles, rituximab may be effective in controlling some but not all non-criteria manifestations of APS (101).

Obstetric considerations

Prophylaxis is recommended for prenatal and postpartum women with APS with no history of thrombosis and full anticoagulation for those with a history of thrombosis.

The administration of low-dose ASA alone for the prevention of fetal loss in women with APS has been associated with an increased frequency of successful pregnancy outcome in some studies (102) but was no better than supportive care in others (103).

  • Low-dose ASA can be stopped any time after 36 weeks of gestation and, ideally, should be stopped 7 to 10 days before delivery as some studies have reported a slight increase in mostly minor perioperative bleeding with continuation of the drug (104). In women with a past history of serious arterial thrombotic complications such as stroke or myocardial infarction, the potential benefit of continuing ASA through labor and delivery outweighs the small risk of incisional bleeding. Aspirin is not usually stopped in these patients. Use of low-dose ASA has not been associated with either premature closure of the ductusarteriosusor or an increase in significant postpartum events.
  • Patients with pregnancy loss receive prophylactic subcutaneous heparin (preferably LMWH) and low-dose aspirin. Therapy is withheld at the time of delivery, restarted after delivery, and continued for at least for 6–12 weeks postpartum.
  • Warfarin (Coumadin) is contraindicated in pregnancy, mainly between 6 and 9 weeks. In a few centers, it is used between 15 and 35 weeks, before and after LMWH.
  • Patients with a history of thrombosis receive therapeutic doses of heparin during pregnancy combined with low-dose aspirin. Long-term anticoagulation is then continued postpartum.
  • Corticosteroids have not been shown to be effective for patients with primary APS and have been shown to increase maternal morbidity and fetal prematurity rates.
  • Breastfeeding women may use heparin, low-dose aspirin, and warfarin.

Caps

  • These patients are generally very ill, often with active SLE.
  • Treatment with intensive anticoagulation, plasma exchange, and corticosteroids appears beneficial, but no controlled trials have been done. Intravenous immunoglobulin may be of some benefit and cyclophosphamide may be considered in selected cases, especially in SLE-associated CAPS.
  • Reports of successful use of rituximab, mainly in hematological complications.

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